Abstract Acquired infections after spinal cord injury (SCI) are prevalent, constitute the main cause of death in patients and have been identified as a modifiable risk factor associated with poor neurological and functional recovery. Infection treatment by orthodox antibiotics is complicated by i) spectrum/efficacy gaps, ii) early development of antibiotic resistancies, and iii) failure of antibiotics to prevent infections when applied early in patients with acute CNS lesions. Moreover, new evidence indicates that antibiotics can impair neurological recovery, due to their ability to cause gut dysbiosis. Improved anti-infective treatment strategies are critically needed, which take the immune-compromised status after SCI into account. Recent data have identified unregulated sympathetic tone originating from below the spinal cord injury site (spinally generated sympathetic nerve activity, SNA) as a major driver of the systemic spinal cord injury immune deficiency syndrome (SCI-IDS). SNA has been identified and independently confirmed as a mechanistic target to restore immune function in vivo. Three aims are proposed to answer one main and novel question: Can immune function and host-defense against pneumonia be re-established with SNA-targeting immunotrophic pharmacological neuromodulation (IPN)? Experiments in Aim 1 will use a novel combination of FDA-approved drugs selected to promote immune system function and reduce susceptibility to bacterial pneumonia acutely or at 4 weeks post SCI. Aim 2 will assess the capacity of IPN to normalize different cellular SCI-IDS characteristics and the sympathetic neuroendocrine reflex. Irrespective of SCI, infections are well-known causes of dysautonomia, which is a pathophysiological conduit for septic conversions. Aim 3 addresses whether IPN can blunt infection-associated autonomic dysfunction and neutralize a sepsis risk factor. If successful, data from these experiments will directly inform effective non-antibiotic anti-infective strategies for SCI patients to reduce infection-associated mortality and disability.